Iron-Catalyzed C(sp²)–C(sp³) Cross-Coupling of Chlorobenzenesulfonamides with Alkyl Grignard Reagents: Entry to Alkylated Aromatics

Abstract

Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the production of pharmaceuticals, agrochemicals, and plasticizers. We report the iron-catalyzed C­(sp2)–​C­(sp3) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and sustainable conditions. Electronically and sterically varied benzosulfonamides as well as challenging alkyl organometallics containing β-hydrogen afford alkylated benzosulfonamides in high to excellent yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and traceless reductive cleavage.

Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Aryl Chlorobenzoates with Alkyl Grignard Reagents

“…We became interested in developing the iron-catalyzed cross-coupling of aryl chlorobenzoates as part of our program in iron catalysis [36][37][38][39][40][41][42][43] and the cross-coupling of C(acyl)-X (X = N, O) electrophiles [44,45]. Recently, several groups have reported methods for the nickel and palladium-catalyzed C(acyl)-O bond activation of aryl benzoates, leading to the selective formation of acyl-metal intermediates (Scheme 2, box) [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64].…”

“…Spectroscopic data matched literature values. General methods have been published [36][37][38][39][40][41][42][43]. All new compounds have been characterized by established guidelines by 1 H-NMR, 13 C-NMR, HRMS, and Mp as appropriate.…”

“…The success of the iron-NMP reagent relies in large part on the outstanding functional group tolerance of this catalyst, the high toxicity of NMP notwithstanding [34,35]. In this vein, our laboratory has reported iron-catalyzed cross-couplings with alkyl Grignard reagents using benign urea ligands that represent an effective alternative to the reprotoxic NMP [36][37][38][39][40][41][42][43].…”

Transition-Metal-Catalyzed Cross-Coupling Reactions of Grignard Reagents

“…In 2019, Szostak and Bisz reported the Fe-catalyzed cross-coupling of chlorobenzenesulfonamides 118 with Grignard reagents 14 under mild and operationally simple reaction conditions to give industrially important alkylated benzenesulfonamides 119 in high to excellent yields (Scheme 54). 123…”

Ligand Effect on Iron‐Catalyzed Cross‐Coupling Reactions: Evaluation of Amides as O‐Coordinating Ligands

“…Next, the generality of these new ligands was evaluated in the cross‐coupling of a chloro‐benzenesulfonamide ( 30 ) (Table ). This class of sulfonamide substrates leads to alkylated benzosulfonamides that show a range of biological properties and serve as traceless groups in the synthesis of alkylbenzenes . We found that several new ligands readily promote the cross‐coupling of 30 at 0.05 mol% loading, with TMU ( 1 ), DEBA ( 4 ) and i Pr‐DMAC ( 16 ) giving the best results.…”